Abstract
Follicular lymphomas (FLs) are slow-growing, indolent tumors containing extensive follicular dendritic cell (FDC) networks and recurrent EZH2 gain-of-function mutations. Paradoxically, FLs originate from highly proliferative germinal center (GC) B cells with proliferation strictly dependent on interactions with T follicular helper cells. Herein, we show that EZH2 mutations initiate FL by attenuating GC B cell requirement for T cell help and driving slow expansion of GC centrocytes that become enmeshed with and dependent on FDCs. By impairing T cell help, mutant EZH2 prevents induction of proliferative MYC programs. Thus, EZH2 mutation fosters malignant transformation by epigenetically reprograming B cells to form an aberrant immunological niche that reflects characteristic features of human FLs, explaining how indolent tumors arise from GC B cells.
Original language | English (US) |
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Pages (from-to) | 655-673.e11 |
Journal | Cancer cell |
Volume | 37 |
Issue number | 5 |
DOIs | |
State | Published - May 11 2020 |
Externally published | Yes |
Keywords
- EZH2
- epigenetic dysregulation
- follicular lymphoma
- germinal center
- immune microenvironment
ASJC Scopus subject areas
- Oncology
- Cancer Research